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Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model

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Abstract

This study examined the interaction characteristics between loreclezole (LCZ) and various conventional antiepileptic drugs (phenytoin - PHT, carbamazepine - CBZ, valproate - VPA and phenobarbital - PB) in the mouse maximal electroshock (MES)-induced seizure model using isobolographic analysis. Drug-related adverse effects were ascertained by use of the chimney test (motor impairment) and the step-through passive avoidance task (learning and retrieval). It was observed that the combination of LCZ with VPA or PB, at the fixed ratio of 1:1, was supra-additive (synergistic) and the combination of LCZ with CBZ, at all fixed ratios tested (1:3, 1:1 and 3:1), was supra-additive against electroconvulsions. The remaining combinations evaluated, i.e., LCZ with PB or VPA at fixed ratios of 1:3 and 3:1, as well as all fixed-ratio combinations between LCZ and PHT, were additive in the MES test in mice. Pharmacokinetic characterization revealed that LCZ significantly increased both free plasma and brain concentrations of CBZ and PHT, but was without effect on PB. Moreover, a bi-directional pharmacokinetic interaction between LCZ and VPA was observed in that while LCZ increased free plasma, but not total brain VPA concentrations, VPA increased the total brain, but not free plasma LCZ concentrations. Adverse-effect testing revealed that for all antiepileptic drug combinations neither motor performance nor long-term memory was altered. Of the drug combinations investigated, only that of LCZ and PB at the fixed ratio of 1:1 was not associated with any pharmacokinetic interactions, and thus it may be concluded that the supra-additive (synergistic) isobolographic interaction was pharmacodynamic in nature. Furthermore, the fact that LCZ and PB have similar mechanisms of action would suggest that drugs with similar mechanisms of action may provide rational polytherapy regimens.

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Acknowledgements

This study was supported by a grant from the Medical University of Lublin. The authors are grateful for the generous gifts of valproate magnesium by ICN Polfa S.A. (Rzeszow, Poland) and carbamazepine by Polfa (Starogard, Poland).

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Authors and Affiliations

  1. Department of Pathophysiology, Medical University of Lublin, Jaczewskiego 8, 20-090, Lublin, Poland

    Jarogniew J. Luszczki & Stanislaw J. Czuczwar

  2. Pharmacology and Therapeutics Unit, Department of Clinical and Experimental Epilepsy, Institute of Neurology, Queen Square, London, WC1N 3BG, UK

    Neville Ratnaraj & Philip N. Patsalos

  3. Department of Physiopathology, Institute of Agricultural Medicine, Jaczewskiego 2, 20-950, Lublin, Poland

    Stanislaw J. Czuczwar

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  1. Jarogniew J. Luszczki
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  2. Neville Ratnaraj
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Correspondence to Jarogniew J. Luszczki.

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Luszczki, J.J., Ratnaraj, N., Patsalos, P.N. et al. Isobolographic analysis of interactions between loreclezole and conventional antiepileptic drugs in the mouse maximal electroshock-induced seizure model. Naunyn Schmied Arch Pharmacol 373, 169–181 (2006). https://doi.org/10.1007/s00210-006-0055-4

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